Pyrazole-derived kinase inhibitors and uses thereof

Details Pyrazole-derived kinase inhibitors and uses thereof Pyrazole-derived kinase inhibitors and uses thereof

2002-08-02

2004-06-15

Desai, Rita (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S364100

Reexamination Certificate

active

06750239

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other disease states that are alleviated by protein kinase inhibitors.
BACKGROUND OF THE INVENTION
Mammalian mitogen-activated protein (MAP) kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995
, J Biol. Chem
., 270, 14843; and Davis, 1995
, Mol. Reprod. Dev
. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK (extracellular signal regulated kinase), JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994
, Cell
76, 1025; Han et al., 1994
, Science
265, 808; Raingeaud et al., 1995
, J Biol. Chem
. 270, 7420; and Shapiro and Dinarello, 1995
, Proc. Natl. Acad. Sci. USA
92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. 1996
, Kidney Int
. 49, 1187).
ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990
, Nature
343, 651; and Crews et al., 1992
, Science
258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995
, J. Biol. Chem
. 270, 18848) and MAPKAP2 (Rouse et al., 1994
, Cell
78, 1027), and transcription factors such as ATF2 (Raingeaud et al., 1996
, Mol. Cell Biol
. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993
Proc. Natl. Acad. Sci. USA
90, 10952), and c-Myc (Oliver et al., 1995
, Proc. Soc. Exp. Biol. Med
. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993
, Science
260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997
, Cancer Res
. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997
, J Clin. Invest
. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997
, Am. J. Respir. Cell Mol. Biol
. 16, 589).
AKT, also known as protein kinase B, is a serine/threonine kinase that plays a central role in promoting the survival of a wide range of cell types (Khwaja, A., 1990
, Nature
, pp. 33-34). It has been shown by Zang et al. that human ovarian cancer cells display elevated levels of AKT-1 and AKT-2. Inhibition of AKT induces apoptosis of these human ovarian cancer cells which demonstrates that AKT may be an important target for ovarian cancer treatment (Zang, Q. Y. et al., 2000
, Oncogene
, 19) and other proliferative disorders. The AKT pathway has also been implicated in motoneuronal survival and nerve regeneration (Kazuhiko, N. et al., 2000
, The Journal of Neuroscience
, 20).
A number of compounds have been developed that purport to specifically inhibit various MAPKs. PCT publication WO 95/31451 describes pyrazole derivatives that inhibit p38. However, it is not clear whether these compounds have the appropriate pharmacological profiles to be therapeutically useful.
Aryl-substituted pyrroles are known in the literature. In particular, tri-aryl pyrroles (U.S. Pat. No. 5,837,719) have been described as having glucagon antagonist activity. 1,5-Diarylpyrazoles have been described as p38 inhibitors (WO 99/58523).
There is a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK activation. For many of these conditions the currently available treatment options are inadequate.
Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK inhibitors, which are useful in treating various conditions associated with protein kinase activation.
SUMMARY OF THE INVENTION
The present invention provides novel classes of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as protein kinase inhibitors. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by protein kinases, including ERK and AKT. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ERK or AKT and inhibiting the activity of that enzyme.
It is a principal object of this invention to provide novel classes of compounds that are protein kinase inhibitors represented by formula I:
or a pharmaceutically acceptable derivative thereof, wherein
B is a phenyl ring having a substituent —L—A and 0-3 R
2
substituents;
L is an optionally substituted C
1
-C
6
alkylidene chain; wherein at least 1 and optionally up to 2 methylene units are replaced by —O—, —C(O)—, —C(O)C(O)—, —C(O)NR
8
—, —C(O)NR
8
NR
8
—, —CO
2
—, —OC(O)—, —NR
8
CO
2
—, —NR
8
C(O)NR
8
—, —OC(O)NR
8
—, —NR
8
—, —NR
8
NR
8
—, —NR
8
CO—, —S—, —SO—, —SO
2
—, —SO
2
NR
8
—, —NR
8
SO
2
—, —NR
8
SO
2
NR
8
—, —N(R
8
)O—, or —ON(R
8
)—;
A is
Q is an optionally substituted C
1
-C
6
alkylidene chain, wherein up to two methylene units are replaced by —C(O)—, —C(O)C(O)—, —C(O)NR
7
—, —C(O)NR
7
NR
7
—, —CO
2
—, —OC(O)—, —NR
7
CO
2
—, —O—, —NR
7
C(O)NR
7
—, —OC(O)NR
7
—, —NR
7
NR
7
—, —NR
7
C(O)—, —S—, —SO—, —SO
2
—, —NR
7
—, —SO
2
NR
7
—, —NR
7
SO
2
—, or —NR
7
SO
2
NR
7
—;
n is zero or one;
R
1
is hydrogen, R, fluoro, —CN, N(R
7
)
2
, OR
7
, NR
7
C(O)R
7
, NR
7
C(O)N(R
7
)
2
, C(O)N(R
7
)
2
, SO
2
R
7
, NR
7
SO
2
R
7
, or SO
2
N (R
7
)
2
;
each R
2
is independently selected from R, OH, OR, SH, SR, nitro, N(R
7
)
2
, halogen, CF
3
, or cyano;
R
3
is hydrogen, R, OH, OR, N(R
7
)
2
, fluoro, or CN;
R
4
is selected from —(CH
2
)
y
R
6
, —(CH
2
)
y
R
10
, —(CH
2
)
y
CH(R
6
)
2
, —(CH
2
)
y
CH (R
10
)
2
, —(CH
2
)
y
CH(R
10
)CH(R
6
)
2
, —(CH
2
)
y
CH(R
10
)(R
6
), —N(R
5
)
2
, or —NR
5
(CH
2
)
y
N(R
5
)
2
;
each R is independently selected from an optionally substituted group selected from C
1-6
aliphatic, C
6-10
aryl, heteroaryl having 5-10 ring atoms, or heterocyclyl having 3-10 ring atoms;
each R
5
is independently selected from R, —(CH
2
)
y
R
6
, —(CH
2
)
y
CH(R
6
)
2
, R
7
, —C(O)R
7
, —CO
2
R
7
, —C(O)N(R
7
)
2
, or —SO
2
R
7
;
each y is independently 0-6;
each R
6
is independently selected from hydrogen, R, —(CH
2
)
y
R, —OH, —OR, —CO
2
R, —(CH
2
)
y
N(R
7
)
2
, —N(R
7
)
2
, —OR
7
, —SR
7
, —NR
7
C(O)R
7
, —NR
7
C(O)N(R
7
)
2
, —C(O)N(R
7
)
2
, —SO
2
R
7
, —NR
7
SO
2
R
7
, —C(O)R
7
, —CN, or —SO
2
N(R
7
)
2
;
each R
7
is independently selected from hydrogen or an optionally substituted C
1-6
aliphatic group, or two R
7
on the same nitrogen are taken together with the nitrogen to optionally form a 5-8 membered heterocyclic or heteroaryl ring;
each R
8
is independently selected from hydrogen, R, —(CH
2
)
y
R
9
, —(CH
2
)
y
CH(R
9
)
2
, —(CH
2
)
y
C(O)R
9
, R
9
, or R
7
;
each R
9
is independently selected from hydrogen, R, —OH, —OR, —SR, —S(O)R, —SO
2
R, —C(O)R
6
, —CO
2
R
6
, NR
2
, halo, cyano, or nitro;
each R
10
is independently selected from R, —(CH
2
)
w
OR
7
, —(CH
2
)
w
N(R
5
)
2
, or —(CH
2
)
w
SR
7
; and
each w is independently 0-4;
provided that when Q
n
—R
4
is
is H, and R
3
is H, and R
2
is a meta substituent Cl, then —L—A is not a para substituent
or
and
when Q
n
—R
4
is
R
1
is NH
2
, R
2
is a meta substituent Cl, and R
3
is H, then —L—A is n

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